To determine the association between the incidence of endometrial cancer and the use of estrogen in menopausal and post-menopausal women, we retrospectively compared 317 patients with adenocarcinoma of the endometrium with an equal number of matched controls having other gynecologic neoplasms; 152 patients used estrogen, as compared to 54 of 317 controls. Thus, the risk of endometrial cancer was 4.5 times greater among women exposed to estrogen therapy. When estrogen use was adjusted for concomitant variables such as obesity, hypertension, diabetes, parity, referral pattern, age at diagnosis, year of diagnosis and other gynecologic neoplasms, the magnitude of the increased relative risk was associated with several of these variables, and was highest in patients without obesity and hypertension. Exogenous estrogen therapy is associated with an increased risk of endometrial carcinoma, but this increased relative risk is less apparent in patients with physiologic characteristics previously associated with an increased risk.